In response to arterial injury, vascular smooth muscle cells (VSMC) proliferate and migrate from the media to transform the intima from essentially a single layer of endothelial cells to a multilayered neointima that subsequently compromises the vascular lumen. Neointimal proliferation plays a critical role in the pathogenesis of atherosclerosis and restenosis after balloon angioplasty and arterial stenting. The fibrinolytic system is activated by vascular injury and plays a major role in modulating the ensuing vascular response. This application will focus on the interconnected functions of plasminogen activator inhibitor-1 (PAl-l), vitronectin, and fibrin(ogen), key components of the fibrinolytic system that appear to play major roles in regulating VSMC function, but whose in vivo actions during neointima development are poorly defined. The Specific Aims of our studies are as follows: Aim 1: Test the hypothesis that PAl-1 mediates the proliferative response to vascular injury by fibrin(ogen)-dependent and fibrin(ogen)-independent pathways. Aim 2. Test the hypothesis that PAI-1-RR (a mutant that lacks anti-proteolytic activity, binds vitronectin normally) can inhibit the pathologic vascular actions of PAl-1 by a dominant negative mechanism. Aim 3. Test the hypothesis that vitronectin modulates the interactions of VSMC with fibrin matrices. We anticipate that these studies will greatly enhance our understanding of the role of the fibrinolytic system in the pathogenesis of neointima formation, and that they may lead to new strategies for treating or preventing this important clinical problem.